UC Santa Cruz scientists advance understanding of Alzheimer’s disease

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UC Santa Cruz scientist Jevgenij Raskatov and grad student Alejandro Rodriguez talk about their Alzheimer’s disease research in a UCSC Physical Sciences Building lab. Raskatov’s team is tweaking the molecules of peptides that accumulate in Alzheimer’s patients, in hopes of eventually reducing their toxicity and accumulation. (Dan Coyro — Santa Cruz Sentinel)

An estimated 5.4 million Americans live with the disease, according to the Alzheimer’s Association. Raskatov’s team is tweaking amyloid beta molecules in hopes of eventually reducing their toxicity and potential to cause disease.

The findings appeared in the journal Chemistry in August.

Amyloid beta is a small sticky protein that clumps together in large wool-like fibrous deposits in the brains of Alzheimer’s patients. Studies suggest these clusters block brain cells from talking to one another, which leads to dementia.

“[Amyloid beta] is believed to be a culprit of Alzheimer’s disease,” said Raskatov, assistant professor of chemistry and biochemistry at UCSC. “But it is exceedingly difficult to study.”

On their way to forming the larger deposits, amyloid beta molecules bundle together into smaller polymers, called oligomers. These are more toxic, unstable and more mobile.

Patients with more oligomers in their brain appear to have greater cognitive decline, said Raskatov.

“It may be that these oligomers may be what kills the neurons,” said Robert Tycko, structural biologist at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, who was not involved in the study. “It’s an idea that’s been around for some time.”

For years, scientists have been trying to study oligomers in the lab. It is challenging because oligomers tend to break down very quickly.

To understand them better, the UCSC team wanted to reconstruct a stable form of the toxic oligomers in the lab. To do this, they tweaked the amyloid beta protein very slightly, a method scientists often use to study complex systems in biology.

“You put in a change and see how the system responds,” said Raskatov. “But you don’t want those changes to be too drastic.”

The researchers switched one of the key amino acids in amyloid beta, called glutamate, with a mirror image molecule.

The modified form of amyloid beta clumped together to form very stable oligomers that were three times to four times more toxic than oligomers detected in Alzheimer’s patients, said Raskatov.

The stable oligomer now gives scientists an opportunity to better understand the nuts and bolts of it.

“It’s a new way of potentially stabilizing the oligomers because then they can be characterized in more detail,” said Tycko. “That would be a valuable application of this kind of approach.”

The UCSC team hopes to further study how the molecule causes Alzheimer’s and identify potential drugs that can reduce the toxicity of amyloid beta.

“We spent all that time creating it, and if we can find out what it is, we can start devising small molecules to destroy it,” Raskatov said. “Those could be disease modifying strategies.”